Focal segmental glomerulosclerosis (FSGS) is a clinical-pathologic syndromes characterized by the accumulation of fibrotic proteins in glomeruli, initially involving only some glomeruli (focal) and involving portions (segments) of the affected glomeruli. FSGS can be classified as follows: idiopathic FSGS, genetic FSGS and post-adaptive FSGS (associated with glomerular hypertrophy and hyperfiltration, and due to reduced renal mass, renal toxins, obesity, and sickle cell disease). A related syndrome is collapsing glomerulopathy, associated with podocyte hyperplasia whereas FSGS is associated with podocyte depletion. Collapsing glomerulopathy can be classified as HIV-associated or idiopathic.[unreadable] [unreadable] The incidence of idiopathic FSGS is increased by a factor of 4 in African Americans, and the incidence of HIV-associated collapsing glomerulpathy is increased by a factor of 18 in African Americans. We are engaged in genetic studies to identify FSGS risk genes. We have found four genes to date: WT1 (Wims tumor-1), WIT1 (Wilms tumor interacting gene-1), PDSS2 (enzyme in the ubiquinone synthesis pathway) land NPHS2 (podocin).[unreadable] [unreadable] A related project pursues that hypothesis that other scarring disorders which are more common in individuals of African descent are associated with genetic mutations. We have identified a number of families of diverse geographical ancestry with familial keloids, and will use genome scans to identify the responsible locus.[unreadable] [unreadable] In order to identify causes of idiopathic collapsing glomerulopathy, we have initiated studies to identify possible viral causes, using blood and urine derived DNA and RNA applied to a viral gene chip.[unreadable] [unreadable] FSGS recurs following renal transplant in approximately 25% of patients, usually during the first 6 months and likely due to a circulating factor. We are currently studying the effect of plasma exchange plus cylosphoshphamide in treating this disorder (N=8). We are also carrying out proteomic profiling of plasma fractions obtained from patients with recurrent FSGS, in order to identify the proteins responsible for glomerular permeability.[unreadable] [unreadable] Our major finding in FY07 arose from a genome scan carried out among 200 African Americans with FSGS and 200 African American blood donors. We used an approach terming mapping by admixture linkage dysequilibrium (MALD), which involved genotyping all subjects for 2000 SNPs which differ significantly (delta of 0.3 or greater) between individuals of African and European descent. We found a locus which links to FSGS and confirmed this linkage in a larger study. The risk for FSGS was 2X for indivdiuals of European descent, 4X for individuals of African descent, and 6X for individuals of African descent who are HIV positive. We are now looking for the specific mutation and studying a relevat animal model.